Abuse-proofed oral dosage form

ABSTRACT

The present invention relates to an abuse-proofed, oral dosage form with controlled opioid-release for once daily administration, characterised in that it comprises at least one opioid with potential for abuse (A), at least one synthetic or natural polymer (C), optionally delayed-release matrix auxiliary substances, physiologically acceptable auxiliary substances (B), optionally a wax (D) and optionally at least one delayed-release coating, component (C) or (D) in each case exhibiting a breaking strength of at least 500 N, preferably of at least 1000 N.

The present invention relates to an abuse-proofed oral dosage form withcontrolled opioid release for once daily administration, comprising atleast one opioid with potential for abuse (A), at least one synthetic ornatural polymer (C), optionally delayed-release matrix auxiliarysubstances, optionally physiologically acceptable auxiliary substances(B), optionally a wax (D) and optionally a delayed-release coating,component (C) or (D) in each case exhibiting a breaking strength of atleast 500 N, preferably of 1000 N.

The name opioids is taken according to the invention to mean compoundswhich interact with at least one opioid receptor. In particular, withthe exception of(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, thephysiologically acceptable salts or derivatives thereof, opioids aretaken to mean those compounds which exhibit a potential for abuse.

Preferably, opioids are used for combatting pain. To this end,analgesics are frequently used in long-term treatment, for example inthe case of chronic pain or pain caused by tumours. In long-termtreatment, in particular, it is important to enable the patient to enjoya good quality of life. The measures which improve the quality of lifeof a patient include dosage forms which allow once daily administration.However, because of the relatively large quantity of opioid, such dosageforms, which provide delayed release of the active ingredient, areparticularly attractive to the abuser who wishes to induce the desiredstate of narcosis or euphoria as quickly as possible.

Since, however, delayed-release dosage forms containing opioids withpotential for abuse do not usually give rise to the kick desired by theabuser when taken orally even in abusively high quantities, these dosageforms for example in the form of tablets or capsules are alsocomminuted, e.g. ground, and sniffed by the abuser for the purpose ofabuse or the active ingredients are extracted from the powder obtainedin this way by means of an aqueous liquid and the resultant solution isadministered parenterally, in particular intravenously, optionally afterfiltration through cotton wool or cellulose wadding. This type ofadministration produces even more accelerated increase in opioid levelsthan with oral or nasal abuse, with the result desired by the abuser,namely the “kick” or “rush”.

U.S. Pat. No. 4,070,494 proposed adding a swellable agent to the dosageform in order to prevent abuse. When water is added to extract theopioid, this agent swells and ensures that the filtrate separated fromthe gel contains only a small quantity of active ingredient.

The multilayer tablet disclosed in WO 95/20947 is based on a similarapproach to preventing parenteral abuse, said tablet containing theopioid with potential for abuse and at least one gel former, each indifferent layers.

WO 03/015531 A2 discloses another approach to preventing parenteralabuse. A dosage form containing an analgesic opioid and a dye as anaversive agent is described therein. The colour released by tamperingwith the dosage form is intended to discourage the abuser from using thedosage form which has been tampered with.

Another known option for complicating abuse involves adding to thedosage form an antagonist to the opioid, such as for example naloxone ornaltexone, or compounds which cause a physiological defence response,such as for example ipecacuanha (ipecac) root, or bitter substances.

However, since in most cases of abuse of dosage forms withdelayed-release of an opioid, it is still necessary to pulverise thedosage form, it was the object of the present invention to complicate orprevent the pulverisation preceding abuse of the dosage form comprisingthe means conventionally available for potential abuse and accordinglyto provide a dosage form with controlled release of opioids withpotential for abuse which ensures the desired therapeutic effect whencorrectly administered once daily, but from which the opioids cannot beconverted into a form suitable for abuse simply by pulverisation.

This object was achieved by the preparation of the abuse-proofed oraldosage form, according to the invention, with controlled release of atleast one opioid for once daily administration, which dosage formcomprises, in addition to at least one opioid and/or at least one of thephysiologically acceptable compounds thereof, preferably salts orderivatives, preferably esters or ethers, with potential for abuse (A),at least one synthetic or natural polymer (C), optionallydelayed-release matrix auxiliary substances, optionally physiologicallyacceptable auxiliary substances (B), optionally a wax (D), andoptionally at least one delayed-release coating, component (C) or (D) ineach case exhibiting a breaking strength of at least 500 N, preferablyof 1000 N.

By using components (C) and optionally (D) with the stated minimumbreaking strength, preferably in such quantities that the dosage formalso exhibits such a minimum breaking strength, pulverisation of thedosage form with conventional means and thus subsequent abuse,preferably nasal or parenteral abuse, may be complicated considerably orprevented.

Preferably, the components (C) and optionally (D) are present in suchquantities that the dosage form exhibits a breaking strength of at least500 N, preferably of at least 1000 N.

Without sufficient comminution of the dosage form, non-hazardousparenteral, in particular intravenous or nasal administration isimpossible or extraction of the active ingredient takes the abuser toolong, or no or an inadequate kick is obtained on abusive oraladministration, since spontaneous release does not occur.

According to the invention, comminution is taken to mean pulverisationof the dosage form with conventional means which are available to anabuser, such as for example a pestle and mortar, a hammer, a mallet orother usual means for pulverisation by application of force.

The dosage form according to the invention is thus suitable forpreventing parenteral, nasal and/or oral abuse of opioids with potentialfor abuse.

Opioids with potential for abuse are known to the person skilled in theart, as are the dosages thereof to be used and processes for theproduction thereof, and may be present in the dosage form according tothe invention as such, in the form of the corresponding derivativesthereof, in particular esters or ethers, or in each case in the form ofcorresponding physiologically acceptable compounds, in particular in theform of the salts or solvates thereof, as racemates or stereoisomers.The dosage form according to the invention is also suitable for theadministration of a plurality of opioids. Preferably it is used toadminister to humans or mammals, preferably to humans, a particularopioid for combatting pain for a duration of at least 24 hours.

The dosage forms according to the invention are very particularlysuitable for preventing the abuse of an opioid which is selected fromthe group consisting ofN-{1-[2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4-methoxymethyl-4-piperidyl}propionanilide(alfentanil), allylprodine, alphaprodine, anileridine, bemidone,benzylmorphine, bezitramide,17-cyclopropylmethyl-4,5a-epoxy-7[(S)-1-hydroxy-1,2,2-trimethyl-propyl]-6-methoxy-6,14-endo-ethanomorphinan-3-ol(buprenorphine), butorphanol, carfentanil, clofedanol, clonitazene,(−)-methyl-[3β-benzoyloxy-2β(1aH,5aH)-tropane carboxylate] (cocaine),4,5a-epoxy-3-methoxy-17-methyl-7-morphinen-6a-ol (codeine),desomorphine, dextromoramide,(+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate(dextropropoxyphene), dezocine, diampromide, diamorphone,4,5a-epoxy-3-methoxy-17-methyl-6a-morphinanol (dihydrocodeine),4,5a-epoxy-17-methyl-3,6a-morphinandiol (dihydromorphine), dimenoxadol,dimephetamol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,dihydromorphone, eptazocine, ethoheptazine, ethylmethylthiambutene,4,5a-epoxy-3-ethoxy-17-methyl-7-morphinen-6a-ol (ethylmorphine),etonitazene,4,5-epoxy-7-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endo-etheno-morphinan-3-ol(etorphine), fenpipramide, N-(1-phenethyl-4-piperidyl)propionanilide(fentanyl), heroin, 4,5-epoxy-3-methoxy-17-methyl-6-morphinanone(hydrocodone), 4,5a-epoxy-3-hydroxy-17-methyl-6-morphinanone(hydromorphone), hydroxypethidine, isomethadone, hydroxymethylmorphinan,1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone (ketobemidone),(3S,6S)-6-dimethylamino-4,4-diphenylheptan-3-yl acetate(levacetylmethadol), (−)-6-dimethylamino-4,4-diphenol-3-heptanone(levomethadone), (−)-17-methyl-3-morphinanol (levorphanol),levophenacylmorphane, levoxemacin, lofentanil, meperidine,2-methyl-2-propyltrimethylene dicarbamate, meptazinol, metazocine,methadone, methylmorphine, metapon, 3-methylfentanyl, 4-methylfentanyl,4,5a-epoxy-17-methyl-7-morphinen-3,6a-diol (morphine), myrophine,nalbuphene, nalorphine, narceine, nicomorphine,6-dimethylamino-4,4-diphenyl-3-hexanone (normethadone), normorphine,norpipanone, the exudation from plants belonging to the species Papaversomniferum (opium),4,5a-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone (oxycodone),oxymorphone, plants and parts of plants belonging to the species Papaversomniferum (including the subspecies setigerum) (Papaver somniferum),papaveretum,1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol(pentazocine),ethyl-(1-methyl-4-phenyl-4-piperidinecarboxylate) (pethidine),phenadoxone, phenomorphane, phenazocine, phenoperidine, piminodine,pholcodeine,1′-(3-cyano-3,3-diphenylpropyl)[1,4′-bipiperidine]-4′-carboxamide(piritramide), proheptazine, promedol, properidine, propoxyphene, methyl(3-[4-methoxycarbonyl-4-(N-phenylpropanamido)piperidino]-propanoate)(remifentanil),N-{4-methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl}propionanilide(sufentanil), ethyl(2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate) (tilidine, cisand trans), tramadol,(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol,(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol,(1S,2S)-3(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,(2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol,(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,preferably as racemate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(4-isobutoxy-phenyl)propionate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(6-methoxy-naphthalen-2-yl)propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(4-isobutyl-phenyl)propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(6-methoxy-naphthalen-2-yl)propionate,(RR-SS)-2-acetoxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-4-chloro-2-hydroxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-4-methyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-4-methoxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-5-nitro-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2′,4′-difluoro-3-hydroxy-biphenyl-4-carboxylic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester togetherwith corresponding stereoisomeric compounds, in each case thecorresponding derivatives thereof, in particular amides, esters orethers, and in each case the physiologically acceptable compoundsthereof, in particular the salts and solvates thereof, particularlypreferably hydrochlorides.

The dosage form according to the invention is particularly suitable forpreventing abuse of an opioid active ingredient selected from among thegroup comprising oxycodone, hydromorphone, morphine, tramadol and thephysiologically acceptable derivatives or compounds thereof, preferablythe salts and solvates thereof, preferably the hydrochlorides thereof.

Furthermore, the dosage form according to the invention is particularlysuitable for preventing the abuse of an opioid active ingredientselected from among the group comprising(2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol,(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol,(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol, the physiologicallyacceptable salts thereof, preferably hydrochlorides, physiologicallyacceptable enantiomers, stereoisomers, diastereomers and racemates andthe physiologically acceptable derivatives thereof, preferably ethers,esters or amides.

These compounds and the process for the production thereof are describedin EP-A-693475 and EP-A-780369 respectively. The correspondingdescriptions are hereby introduced as a reference and are deemed to bepart of the disclosure.

The dosage in the delayed-release dosage form is selected such that oncedaily administration is ensured. The corresponding dosages are known tothe person skilled in the art.

In order to achieve the necessary breaking strength of the dosage formaccording to the invention, at least one synthetic, semi-synthetic ornatural polymer (C) is used which has a breaking strength, measuredusing the method disclosed in the present application, of at least 500N, preferably of 1000 N. Preferably, at least one polymer is selectedfor this purpose from among the group comprising polyalkylene oxides,preferably polymethylene oxides, polyethylene oxides, polypropyleneoxides, polyolefins, preferably polyethylenes, polypropylenes, polyvinylchlorides, polycarbonates, polystyrenes, polymethacrylates, thecopolymers thereof, and mixtures of at least two of the stated polymerclasses or polymers. Particularly preferably, a water-soluble orwater-swellable polymer is used. The polymers are distinguished by amolecular weight of at least 0.5 million, preferably of at least 1million to 15 million, determined by theological measurement.Particularly preferably suitable are thermoplastic polyalkylene oxides,such as polyethylene oxides, with a molecular weight of at least 0.5million, preferably of at least 1 million to 15 million, determined byrheological measurement. The polyethylene oxides have a viscosity at 25°C. of 4500 to 17600 cP, measured on a 5 wt. % aqueous solution using amodel RVF Brookfield viscosimeter (spindle no. 2/rotational speed 2rpm), of 400 to 4000 cP, measured on a 2 wt. % aqueous solution usingthe stated viscosimeter (but with spindle no. 1 or 3/rotational speed 10rpm) or of 1650 to 10000 cP, measured on a 1 wt. % aqueous solutionusing the stated viscosimeter (but with spindle no. 2/rotational speed 2rpm).

The polymers are preferably used as powder to produce the dosage formaccording to the invention.

Moreover, in addition to the above-stated polymers, at least onenatural, semi-synthetic or synthetic wax (D) with a breaking strength,measured using the method disclosed in the present application, of atleast 500 N, preferably of 1000 N, may additionally be used to achievethe necessary breaking strength of the dosage form according to theinvention. Waxes with a softening point of at least 60° C. arepreferred. Carnauba wax and beeswax are particularly preferred. Carnaubawax is very particularly preferred. Carnauba wax is a natural wax whichis obtained from the leaves of the carnauba palm and has a softeningpoint of at most 90° C. When additionally using the wax component, thelatter is used together with at least one polymer (C), preferably apolyethylene oxide, in such quantities that the dosage form exhibits abreaking strength of at least 500 N, preferably of 1000 N, measuredusing the method stated in the present application.

The dosage forms according to the invention are distinguished in that,they cannot be pulverised using conventional comminution tools, such asgrinders, due to their hardness. Oral, parenteral, in particularintravenous, or nasal abuse is complicated a very great deal thereby, ifnot ruled out altogether. However, in order to prevent any possibleabuse of the dosage forms according to the invention, in a preferredembodiment, the dosage forms according to the invention may containfurther abuse-complicating or -preventing agents as auxiliary substances(B).

Thus, the abuse-proofed dosage form according to the invention maycomprise, in addition to at least one opioid, at least one polymer (C)and optionally at least one wax (D), at least one of the followingcomponents (a)-(f) as auxiliary substances (B):

-   (a) at least one substance which irritates the nasal passages and/or    pharynx,-   (b) at least one viscosity-increasing agent, which, with the    assistance of a necessary minimum quantity of an aqueous liquid,    preferably as an aqueous extract obtained from the dosage form,    forms a gel which preferably remains visually distinguishable when    introduced into a further quantity of an aqueous liquid,-   (c) at least one antagonist for the present opioids with potential    for abuse,-   (d) at least one emetic,-   (e) at least one dye as an aversive agent,-   (f) at least one bitter substance.

The components (a) to (f) are each suitable on their own as additionalprotection of the dosage form according to the invention against abuse.Accordingly, component (a) is preferably suitable for proofing thedosage form against nasal, oral and/or parenteral, preferablyintravenous, abuse, component (b) is preferably suitable for proofingagainst parenteral, particularly preferably intravenous and/or nasalabuse, component (c) is preferably suitable for proofing against nasaland/or parenteral, particularly preferably intravenous, abuse, component(d) is preferably suitable for proofing against parenteral, particularlypreferably intravenous, and/or oral and/or nasal abuse, component (e) issuitable as a visual deterrent against oral or parenteral abuse andcomponent (f) is suitable for proofing against oral or nasal abuse.Through the co-use of at least one of the above-stated components, it ispossible to complicate abuse even more effectively for the dosage formsaccording to the invention.

In one embodiment, the dosage form according to the invention may alsocomprise two or more of components (a)-(f) in a combination, preferablyin the combinations (a), (b) and optionally (c) and/or (f) and/or (e) or(a), (b) and optionally (d) and/or (f) and/or (e).

In another embodiment, the dosage form according to the invention maycomprise all of components (a)-(f).

If the dosage form according to the invention comprises component (a) asadditional protection against abuse, substances which irritate the nasalpassages and/or pharynx which may be considered according to theinvention are any substances which, when administered via the nasalpassages and/or pharynx, bring about a physical reaction which is eitherso unpleasant for the abuser that he/she does not wish to or cannotcontinue administration, for example burning, or physiologicallycounteracts taking of the corresponding opioid(s) and/or opiate(s), forexample due to increased nasal secretion or sneezing. These substanceswhich conventionally irritate the nasal passages and/or pharynx may alsobring about a very unpleasant sensation or even unbearable pain whenadministered parenterally, in particular intravenously, such that theabuser does not wish to or cannot continue taking the substance.

Particularly suitable substances which irritate the nasal passagesand/or pharynx are those which cause burning, itching, an urge tosneeze, increased formation of secretions or a combination of at leasttwo of these stimuli. Appropriate substances and the quantities thereofwhich are conventionally to be used are known per se to the personskilled in the art or may be identified by simple preliminary testing.

The substance which irritates the nasal passages and/or pharynx ofcomponent (a) is preferably based on one or more constituents or one ormore plant parts of at least one hot substance drug.

Corresponding hot substance drugs are known per se to the person skilledin the art and are described, for example, in “PharmazeutischeBiologie—Drogen and ihre Inhaltsstoffe” by Prof. Dr. Hildebert Wagner,2nd., revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982,pages 82 et seq. The corresponding description is hereby introduced as areference and is deemed to be part of the disclosure.

One or more constituents of at least one hot substance drug selectedfrom the group consisting of Allii sativi bulbus (garlic), Asari rhizomacum herba (Asarum root and leaves), Calami rhizoma (calamus root),Capsici fructus (capsicum), Capsici fructus acer (cayenne pepper),Curcumae longae rhizoma (turmeric root), Curcumae xanthorrhizae rhizoma(Javanese turmeric root), Galangae rhizoma (galangal root), Myristicaesemen (nutmeg), Piperis nigri fructus (pepper), Sinapis albae semen(white mustard seed), Sinapis nigri semen (black mustard seed),Zedoariae rhizoma (zedoary root) and Zingiberis rhizoma (ginger root),particularly preferably from the group consisting of Capsici fructus(capsicum), Capsici fructus acer (cayenne pepper) and Piperis nigrifructus (pepper) may preferably be added as component (a) to the dosageform according to the invention.

The constituents of the hot substance drugs preferably compriseo-methoxy(methyl)phenol compounds, acid amide compounds, mustard oils orsulfide compounds or compounds derived therefrom.

Particularly preferably, at least one constituent of the hot substancedrugs is selected from the group consisting of myristicin, elemicin,isoeugenol, a-asarone, safrole, gingerols, xanthorrhizol, capsaicinoids,preferably capsaicin, capsaicin derivatives, such asN-vanillyl-9E-octadecenamide, dihydrocapsaicin, nordihydrocapsaicin,homocapsaicin, norcapsaicin and nomorcapsaicin, piperine, preferablytrans-piperine, glucosinolates, preferably based on non-volatile mustardoils, particularly preferably based on p-hydroxybenzyl mustard oil,methylmercapto mustard oil or methylsulfonyl mustard oil, and compoundsderived from these constituents.

The dosage form according to the invention may preferably contain theplant parts of the corresponding hot substance drugs in a quantity of0.01 to 30 wt. %, particularly preferably of 0.1 to 0.5 wt. %, in eachcase relative to the total weight of the dosage unit. If one or moreconstituents of corresponding hot substance drugs are used, the quantitythereof in a dosage unit according to the invention preferably amountsto 0.001 to 0.005 wt. %, relative to the total weight of the dosageunit. A dosage unit is taken to mean a separate or separableadministration unit, such as for example a tablet or a capsule.

Another option for preventing abuse of the dosage form according to theinvention consists in adding at least one viscosity-increasing agent asa further abuse-preventing component (b) to the dosage form, which, withthe assistance of a necessary minimum quantity of an aqueous liquid,preferably as an aqueous extract obtained from the dosage form, forms agel which is virtually impossible to administer safely and preferablyremains visually distinguishable when introduced into a further quantityof an aqueous liquid

For the purposes of the present application, visually distinguishablemeans that the opioid- or opiate-containing gel formed with theassistance of a necessary minimum quantity of aqueous liquid, whenintroduced, preferably with the assistance of a hypodermic needle, intoa further quantity of aqueous liquid at 37° C., remains substantiallyinsoluble and cohesive and cannot straightforwardly be dispersed in sucha manner that it can safely be administered parenterally, in particularintravenously. The material preferably remains visually distinguishablefor at least one minute, preferably for at least 10 minutes.

Increasing the viscosity to a gel makes it more difficult or evenimpossible for it to be passed through a needle or injected. If the gelremains visually distinguishable, this means that the gel obtained onintroduction into a further quantity of aqueous liquid, for example byinjection into blood, initially remains in the form of a largelycohesive thread, which, while it may indeed be broken up mechanicallyinto smaller fragments, cannot be dispersed or even dissolved in such amanner that it can safely be administered parenterally, in particularintravenously. In combination with at least one further presentcomponent (a), (d) to (f), this additionally leads to unpleasantburning, vomiting, bad flavour and/or visual deterrence.

Intravenous administration of such a gel would most probably result inobstruction of blood vessels, associated with serious damage to thehealth of the abuser.

In order to verify whether a viscosity-increasing agent is suitable ascomponent (b) for use in the dosage form according to the invention, theopioid(s) and/or opiate(s) is(are) mixed with the viscosity-increasingagent and suspended in 10 ml of water at a temperature of 25° C. If thisresults in the formation of a gel which fulfils the above-statedconditions, the corresponding viscosity-increasing agent is suitable foradditionally preventing or averting abuse of the dosage forms accordingto the invention.

If component (b) is added to the dosage form obtained by the processaccording to the invention, preferably one or more viscosity-increasingagents are used, which are selected from the group comprisingmicrocrystalline cellulose with 11 wt. % carboxymethylcellulose sodium(Avicel® RC 591), carboxymethylcellulose sodium (Blanose®, CMC-NaC300P®, Frimulsion BLC-5®, Tylose C300 P®), polyacrylic acid (Carbopol®980 NF, Carbopol® 981), locust bean flour (Cesagum® LA-200, Cesagum®LID/150, Cesagum® LN-1), pectins, preferably from citrus fruits orapples (Cesapectin® HM Medium Rapid Set), waxy maize starch (C*Gel04201®), sodium alginate (Frimulsion ALG (E401)®), guar flour(Frimulsion BM®, Polygum 26/1-75®), iota-carrageenan (Frimulsion D021®),karaya gum, gellan gum (Kelcogel F®, Kelcogel LT100®), galactomannan(Meyprogat 150®), tara stone flour (Polygum 43/1®), propylene glycolalginate (Protanal-Ester SD-LB®), sodium-hyaluronate, tragacanth, taragum (Vidogum SP 200®), fermented polysaccharide welan gum (K1A96),xanthans such as xanthan gum (Xantural 180®). Xanthans are particularlypreferred. The names stated in brackets are the trade names by which thematerials are known commercially. In general, a quantity of 0.1 to 5 wt.%, relative to the total quantity of the dosage form, of the statedviscosity-increasing agent(s) is sufficient to fulfil the above-statedconditions.

The component (b) viscosity-increasing agents, where provided, arepreferably present in the dosage form according to the invention inquantities of=5 mg per dosage unit, i.e. per administration unit.

In a particularly preferred embodiment of the present invention, theviscosity-increasing agents used as component (b) are those which,preferably by extraction from the dosage form with the necessary minimumquantity of aqueous liquid, form a gel which encloses air bubbles. Theresultant gels are distinguished by a turbid appearance, which providesthe potential abuser with an additional optical warning and discourageshim/her from administering the gel parenterally.

The component (C) may also optionally serve as an additionalviscosity-increasing agent, which forms a gel with the assistance of anecessary minimum quantity of aqueous liquid.

It is also possible, to arrange the viscosity-increasing component andthe other constituents of the dosage form according to the inventionspatially separately from one another.

Moreover, in order to discourage and prevent abuse, the dosage formaccording to the invention may furthermore comprise component (c),namely one or more antagonists for the opioid(s) and/or opiate(s) withpotential for abuse, wherein the antagonist is preferably spatiallyseparated from the remaining constituents of the dosage form accordingto the invention and, when correctly used, do not exert any effect.

Suitable antagonists for preventing the abuse of opioids are known perse to the person skilled in the art and may be present in the dosageform according to the invention as such or in the form of correspondingderivatives, in particular esters or ethers, or in each case in the formof corresponding physiologically acceptable compounds, in particular inthe form of the salts or solvates thereof.

The antagonist used is preferably selected from the group comprisingnaloxone, naltrexone, nalmefene, nalide and nalmexone, in each caseoptionally in the form of a corresponding physiologically acceptablecompound, in particular in the form of a base, a salt or solvate. Thecorresponding antagonists, where component (c) is provided, arepreferably used in a quantity of=1 mg, particularly preferably in aquantity of 3 to 100 mg, very particularly preferably in a quantity of 5to 50 mg per dosage form, i.e. per administration unit.

The dosage form according to the invention preferably comprises theantagonist component in a conventional therapeutic dose known to theperson skilled in the art, particularly preferably in a quantity oftwice to three times this dose per administration unit.

If the combination for additional discouragement and prevention of abuseof the dosage form according to the invention comprises component (d),it may comprise at least one emetic, which is preferably present in aspatially separated arrangement from the other components of the dosageform according to the invention and, when correctly used, is intendednot to exert its effect in the body.

Suitable emetics for additionally preventing abuse of an opioid areknown per se to the person skilled in the art and may be present in thedosage form according to the invention as such or in the form ofcorresponding derivatives, in particular esters or ethers, or in eachcase in the form of corresponding physiologically acceptable compounds,in particular in the form of the salts or solvates thereof.

An emetic based on one or more constituents of ipecacuanha (ipecac)root, preferably based on the constituent emetine may preferably beconsidered for the dosage form according to the invention, as are, forexample, described in “Pharmazeutische Biologie—Drogen and ihreInhaltsstoffe” by Prof. Dr. Hildebert Wagner, 2nd, revised edition,Gustav Fischer Verlag, Stuttgart, New York 1982. The correspondingliterature description is hereby introduced as a reference and is deemedto be part of the disclosure.

The dosage form according to the invention may preferably comprise theemetic emetine as component (d), preferably in a quantity of=3 mg,particularly preferably of=10 mg and very particularly preferably in aquantity of=20 mg per dosage form, i.e. administration unit.

Apomorphine may likewise preferably be used as an emetic for additionalabuse-proofing, preferably in a quantity of preferably=3 mg,particularly preferably of=5 mg and very particularly preferably of=7 mgper administration unit.

If the dosage form according to the invention contains component (e) asa further abuse-preventing auxiliary substance, the use of such a dyebrings about an intense coloration of a corresponding aqueous solution,in particular when the attempt is made to extract the opioid(s) forparenteral, preferably intravenous administration, which coloration mayact as a deterrent to the potential abuser. Oral abuse, whichconventionally begins by means of aqueous extraction of the opioid(s),may also be prevented by this coloration. Suitable dyes and thequantities required for the necessary deterrence may be found in WO03/015531, wherein the corresponding disclosure should be deemed to bepart of the present disclosure and is hereby introduced as a reference.

If the dosage form according to the invention contains component (f) asa further abuse-preventing auxiliary substance, this addition of atleast one bitter substance and the consequent impairment of the flavourof the dosage form additionally prevents oral and/or nasal abuse.

Suitable bitter substances and the quantities effective for use may befound in US-2003/0064099, the corresponding disclosure of which shouldbe deemed to be the disclosure of the present application and is herebyintroduced as a reference. Suitable bitter substances are preferablyaromatic oils, preferably peppermint oil, eucalyptus oil, bitter almondoil, menthol, fruit aroma substances, preferably aroma substances fromlemons, oranges, limes, grapefruit or mixtures thereof, and/ordenatonium benzoate (Bitrex®). Denatonium benzoate is particularlypreferably used.

To ensure once daily administration, the dosage form according to theinvention comprises the opioid (s) and/or opiate(s) with potential forabuse at least in part in delayed-release form, wherein the delayedrelease of the active ingredient may be achieved with the assistance ofconventional materials and processes known to the person skilled in theart, for example by embedding the opioid(s) in a delayed-release matrixor by applying one or more delayed-release coatings. Opioid releasemust, however, be controlled such that the above-stated conditions arefulfilled in each case, for example that, in the event of correctadministration of the dosage form, the opioid(s) are virtuallycompletely released before the optionally present component (c) and/or(d) can exert an impairing effect. In particular, release of the opioidmust ensure analgesic action for at least 24 hours.

If release of the opioid(s) from the dosage form according to theinvention is controlled with the assistance of at least onedelayed-release coating, the delayed-release coating may consist ofconventional materials known to the person skilled in the art.

In a preferred embodiment of the dosage form according to the invention,the delayed-release coating is preferably based on a water-insoluble,optionally modified natural and/or synthetic polymer or on a natural,semi-synthetic or synthetic wax or on a fat or a fatty alcohol or on amixture of at least two of the above-stated components.

To produce a delayed-release coating, the water-insoluble polymerspreferably comprise poly(meth)acrylates, particularly preferablypoly(C₁₋₄-alkyl(meth)acrylates,poly(C₁₋₄)-dialkylamino-(C₁₋₄)-alkyl(meth)acrylates and/or thecopolymers thereof, very particularly preferably copolymers of ethylacrylate and methyl methacrylate with a molar ratio of monomers of 2:1(Eudragit NE30D®), copolymers of ethyl acrylate, methyl methacrylate andtrimethylammonium methyl methacrylate chloride with a molar ratio ofmonomers of 1:2:0.1 (Eudragit RS®), copolymers of ethyl acrylate, methylmethacrylate and trimethylammonium methyl methacrylate chloride with amolar ratio of monomers of 1:2:0.2 (Eudragit RL®) or a mixture of atleast two of these above-stated copolymers. These coating materials arecommercially obtainable as 30 wt. % aqueous latex dispersions, i.e. asEudragit RS30D®, Eudragit NE30D® or Eudragit RL30D® and are preferablyalso used as such as coating material.

Polyvinyl acetates optionally in combination with further auxiliarysubstances may likewise preferably be used as water-insoluble polymersfor the production of a delayed-release coating for the dosage formsaccording to the invention. These are commercially obtainable as aqueousdispersions containing 27 wt. % of polyvinyl acetate, 2.5 wt. % ofpovidone and 0.3 wt. % of sodium lauryl sulfate (Kollicoat SR 30 D®).

In a further preferred embodiment, the delayed-release coatings for thedosage form according to the invention are based on water-insolublecellulose derivatives, preferably alkylcelluloses such as for exampleethylcellulose, or cellulose esters, such as for example celluloseacetate. The coatings of ethylcellulose or cellulose acetate arepreferably applied from an aqueous pseudolatex dispersion. Aqueousethylcellulose pseudolatex dispersions are commercially obtainable as 30wt. % dispersions (Aquacoat®) or as 25 wt. % dispersions (Surelease®).

If the delayed-release coating is based a water-insoluble, optionallymodified natural and/or synthetic polymer, the coating dispersion orsolution may comprise, in addition to the corresponding polymer, aconventional physiologically acceptable plasticiser known to the personskilled in the art, in order to reduce the necessary minimum filmtemperature.

Suitable plasticisers are for example lipophilic diesters from analiphatic or aromatic dicarboxylic acid with C₆-C₄₀ and an aliphaticalcohol with C₁-C₈, such as for example dibutyl phthalate, diethylphthalate, dibutyl sebacate or diethyl sebacate, hydrophilic orlipophilic esters of citric acid, such as triethyl citrate, tributylcitrate, acetyl tributyl citrate or acetyl triethyl citrate,polyethylene glycols, propylene glycol, esters of glycerol, such as forexample triacetin, Myvacet® (acetylated mono- and diglycerides, C₂₃H₄₄O₅to C₂₅H₄₇O₇), medium-chain triglycerides (Miglyol®), oleic acid ormixtures of at least two of the stated plasticisers. Aqueous dispersionsof Eudragit RS® and optionally Eudragit RL® preferably contain triethylcitrate.

Preferably, a delayed-release coating for the dosage form according tothe invention contains plasticisers in quantities of 5 to 50 wt. %,particularly preferably of 10 to 40 wt. % and very particularlypreferably of 10 to 30 wt. %, relative to the quantity of polymer used.In individual cases, for example for cellulose acetate, it is alsopossible to use larger quantities of plasticisers.

Moreover, a delayed-release coating may comprise further conventionalauxiliary substances known to the person skilled in the art, such as forexample slip agents, preferably talcum or glycerol monostearate,colouring pigments, preferably iron oxides or titanium dioxide, orsurfactants, such as for example Tween 80®.

The release profile obtained for the opioid(s) may furthermore beadjusted by conventional options known to the person skilled in the art,such as for example the thickness of the coating or by the use offurther auxiliary substances as constituents of the coating. Suitableauxiliary substances are for example hydrophilic or pH-dependent poreformers, such as for example sodium carboxymethylcellulose, celluloseacetate phthalate, hydroxypropylmethylcellulose acetate succinate,lactose, polyethylene glycol or mannitol or water-soluble polymers, suchas for example polyvinylpyrrolidone or water-soluble celluloses,preferably hydroxypropylmethylcellulose or hydroxypropylcellulose.

The dosage forms according to the invention for release of the opioids)may additionally also comprise a coating which is resistant to gastricjuices, which dissolves in pH-dependent manner. This coating makes itpossible to ensure that the dosage forms according to the invention passthrough the stomach undissolved and the opioid(s) is(are) not releaseduntil it(they) reach(es) the intestine.

The coating resistant to gastric juices is preferably based onmethacrylic acid/alkyl methacrylate copolymers, preferably methylmethacrylate, such as methacrylic acid or ethylene methacrylatecopolymers with a molar ratio of the particular monomers of 1:1 to 1:2,such as Eudragit L®, Eudragit S®, Eudragit L30D-55®, Eudragit FS®.

A delayed-release coating may be applied by conventional methods knownto the person skilled in the art, such as for example by spraying ofsolutions, dispersions or suspensions, by melt methods or by powderapplication methods. The solutions, dispersions or suspensions may beused in the form of aqueous or organic solutions or dispersions. Aqueousdispersions are preferably used in this connection. Organic solventswhich may be used are alcohols, for example ethanol or isopropanol,ketones, such as for example acetone, esters, for example ethyl acetate,wherein alcohols and ketones are preferably used. The coating methodsare known from the prior art, for example H. Sucker, Georg ThiemeVerlag, 1991, pages 347 et seq. They are hereby introduced as areference and are accordingly deemed to be part of the disclosure.

If the dosage form according to the invention is in multiparticulateform, the delayed-release coating is preferably applied in such a mannerthat the multiparticulate forms containing the opioid(s) are coated,after the production thereof, with the particular polymers andoptionally further auxiliary substances from aqueous and/or organicmedia, preferably from aqueous media, with the assistance of thefluidised bed method and the coating is preferably simultaneously driedat conventional temperatures in the fluidised bed.

A poly(meth)acrylate-based coating is preferably dried at temperaturesin the range from 30 to 50° C., particularly preferably from 35 to 45°C. For cellulose-based coatings, such as for example ethylcellulose,drying preferably proceeds at a temperature in the range from 50 to 80°C., particularly preferably in the range from 55 to 65° C. If necessary,drying may additionally be followed by a temperature-controlledtreatment in order to obtain a stable release profile.

Delayed release of the active ingredient from the dosage form accordingto the invention may also be achieved by embedding the opioid(s) in adelayed-release matrix.

Materials which may be used for a delayed-release matrix are preferablyphysiologically acceptable, hydrophilic polymers, preferably celluloseethers, cellulose esters and/or acrylic resins. Ethylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxyethylcellulose, methylcellulose, poly(meth)acrylic acid and/orthe derivatives thereof, such as the salts, amides or esters thereof,are particularly preferably used.

Where hydrophobic compounds are used as the delayed-release matrix,fatty acids, fatty alcohols or corresponding esters or ethers ormixtures thereof may be used. Mono- or diglycerides of C12-C30 fattyacids and/or C12-C30 fatty alcohols and/or waxes or mixtures thereof areparticularly preferably used as hydrophobic compounds.

It is also possible to use mixtures of the above-stated hydrophilic andhydrophobic matrix materials.

Component (b) as a viscosity-increasing agent may preferably also serveas a material for a delayed-release matrix, if this is permitted by thestructure of the dosage form according to the invention.

Component (C) and the optionally present component (D), which serve toobtain the breaking strength of at least 500 N, preferably of 1000 N,which is necessary according to the invention, may optionally also serveas additional delayed-release matrix materials.

Corresponding delayed-release compounds and methods for the delayedrelease of the dosage forms according to the invention and for theapplication of coatings which are resistant to gastric juices are knownto the person skilled in the art, for example from “CoatedPharmaceutical Dosage Forms—Fundamentals, Manufacturing Techniques,Biopharmaceutical Aspects, Test Methods and Raw Materials” by Kurt H.Bauer, K. Lehmann, Hermann P. Osterwald, Rothgang, Gerhart, 1st edition,1998, Medpharm Scientific Publishers. The corresponding literaturedescription is hereby introduced as a reference and is deemed to be partof the disclosure.

The dosage form according to the invention may assume multiparticulateform, preferably the form of microtablets, micropellets, granules,spheroids, beads or pellets, optionally packaged in capsules orpress-moulded into tablets. The multiparticulate forms preferably have asize or size distribution in the range from 0.1 to 3 mm, particularlypreferably in the range from 0.5 to 2 mm. Depending on the desireddosage form, conventional auxiliary substances (B) are optionally alsoused for the formulation of the dosage form.

In a particularly preferred embodiment, the dosage form according to theinvention assumes the form of a tablet, a capsule or is in the form ofan oral osmotic therapeutic system (OROS), preferably if at least onefurther abuse-preventing component (a)-(f) is also present.

The abuse-proofed, solid dosage form according to the invention ispreferably produced by mixing components (A), (C) and optionally (D),optionally at least one of the additional abuse-preventing components(a)-(f) and optionally further auxiliary substances (B), in particularthe delayed-release matrix compounds, and, with preceding orsimultaneous exposure to heat, forming the resultant mixture, optionallyafter pelletisation, into the dosage form by application of force.

Pelletisation may be performed by a melt method or by wet pelletisation.

Mixing of components (A), (C) and optionally (D) and of the optionallypresent further components (a)-(f) and optionally the further auxiliarysubstances (B), in particular the delayed-release matrix compounds, mayproceed in a mixer known to the person skilled in the art. The mixermay, for example, be a roll mixer, shaking mixer, shear mixer orcompulsory mixer.

The resultant mixture is preferably directly formed into the dosage formaccording to the invention by application of force with preceding orsimultaneous exposure to heat. The mixture may, for example, be formedinto tablets by direct tabletting. In direct tabletting with precedingexposure to heat, the material to be press-moulded is heated immediatelyprior to tabletting at least to the softening temperature of component(C) and then pressed.

The resultant mixture of components (A), (C), optionally (D), theoptionally present components (a) to (f) and optionally furtherauxiliary substances (B), in particular the delayed-release matrixcompounds, may also first be pelletised and then formed into the dosageform according to the invention by application of force with precedingor simultaneous exposure to heat.

It is also possible to form the resultant mixture containing one or moreopioid(s) with potential for abuse (A) and optionally physiologicallyacceptable auxiliary substances (B), such as components (a) to (f) andoptionally the delayed-release matrix compounds and at least onesynthetic or natural polymer (C) and optionally a wax (D), into thedosage form by application of force, optionally to singulate the formedarticles and optionally in each case to grade them by size and, after orduring heating to at least the softening point of component (C), toexpose them to force until the formed articles exhibit a breakinghardness of at least 500 N, preferably of 1000 N, optionally to providethem with a cover, which optionally has delayed-release properties, andoptionally to mix all the formed articles together again.

If components (c) and/or (d) and/or (f) are present in the dosage formaccording to the invention, care must be taken to ensure that they areformulated in such a manner or are present in such a low dose that, whencorrectly administered, the dosage form is able to bring about virtuallyno effect which impairs the patient or the efficacy of the opioid(s).

If the dosage form according to the invention contains component (d)and/or (f), the dosage must be selected such that, when correctly orallyadministered, no negative effect is caused. If, however, the intendeddosage of the dosage form is exceeded inadvertently, in particular bychildren, or in the event of abuse, nausea or an inclination to vomit ora bad flavour are produced. The particular quantity of component (d)and/or (f) which can still be tolerated by the patient in the event ofcorrect oral administration may be determined by the person skilled inthe art by simple preliminary testing.

If, however, irrespective of the fact that the dosage form according tothe invention is virtually impossible to pulverise, the dosage formcontaining the components (c) and/or (d) and/or (f) is provided withprotection, these components should preferably be used at a dosage whichis sufficiently high that, when abusively administered, they bring aboutan intense negative effect on the abuser. This is preferably achieved byspatial separation of at least the opioid(s) from components (c) and/or(d) and/or (f), wherein the opioid(s) is/are present in at least onesubunit (X) and components (c) and/or (d) and/or (f) is/are present inat least one subunit (Y), and wherein, when the dosage form is correctlyadministered, components (c), (d) and (f) do not exert their effect ontaking and/or in the body and the remaining components of theformulation, in particular component (C), are identical.

If the dosage form according to the invention comprises at least 2 ofcomponents (c) and (d) or (f), these may each be present in the same ordifferent subunits (Y). Preferably, when present, all the components (c)and (d) and (f) are present in one and the same subunit (Y).

In the case of spatial separation into subunit(s) (X) and subunit(s) (Y)and irrespective of the arrangement of these subunits in the dosageform, a subunit (X) contains the active ingredient in delayed-releaseform, such that said active ingredient ensures controlled release withonce daily administration.

For the purposes of the present invention, subunits are solidformulations, which in each case, apart from conventional auxiliarysubstances known to the person skilled in the art, contain theopioid(s), at least one polymer (C) and optionally at least one of theoptionally present components (a) and/or (b) and/or (e) or in each caseat least one polymer (C) and the antagonist(s) and/or emetic(s) and/orcomponent (e) and/or component (f) and optionally at least one of theoptionally present components (a) and/or (b) and optionally thedelayed-release matrix compounds. Care must here be taken to ensure thateach of the subunits is formulated in accordance with the above-statedprocess.

One substantial advantage of the separated formulation of the opioid(s)from components (c) or (d) or (f) in subunits (X) and (Y) of the dosageform according to the invention is that, when correctly administered,components (c) and/or (d) and/or (f) are hardly released on takingand/or in the body or are released in such small quantities that theyexert no effect which impairs the patient or therapeutic success or, onpassing through the patient's body, they are only liberated in locationswhere they cannot be sufficiently absorbed to be effective. When thedosage form is correctly administered, preferably hardly any ofcomponents (c) and/or (d) and/or (f) is released into the patient's bodyor they go unnoticed by the patient.

The person skilled in the art will understand that the above-statedconditions may vary as a function of the particular components (c), (d)and/or (f) used and of the formulation of the subunits or the dosageform. The optimum formulation for the particular dosage form may bedetermined by simple preliminary testing. What is vital is that eachsubunit contains the polymer (C) and has been formulated in the statedmanner.

Should, contrary to expectations, the abuser succeed in comminuting sucha dosage form according to the invention, which comprises components (c)and/or (e) and/or (d) and/or (f) in subunits (Y), for the purpose ofabusing the opioid(s) and obtain a powder which is to be extracted witha suitable extracting agent, not only the opioid(s) but also theparticular component (c) and/or (e) and/or (f) and/or (d) will beobtained in a form in which it cannot readily be separated from theopioid(s), such that when the dosage form which has been tampered withis administered, in particular by oral and/or parenteral administration,it will exert its effect immediately on taking and/or in the bodycombined with an additional negative effect on the abuser correspondingto component (c) and/or (d) and/or (f) or, when the attempt is made toextract the active ingredient, the coloration will act as a deterrentand so prevent abuse of the dosage form.

A dosage form according to the invention, in which the opioid(s) is/arespatially separated from components (c), (d) and/or (e), preferably byformulation in different subunits, may be formulated in many differentways, wherein the corresponding subunits may each be present in thedosage form according to the invention in any desired spatialarrangement relative to one another, provided that the above-statedconditions for the release of components (c) and/or (d), on the onehand, and for release of the opioid, namely controlled release for oncedaily administration, on the other, are fulfilled.

The person skilled in the art will understand that component(s) (a)and/or (b) which are optionally also present may preferably beformulated in the dosage form according to the invention both in theparticular subunits (X) and (Y) and in the form of independent subunits(Y′) corresponding to subunits (X) and (Y), provided that neither theabuse-proofing nor the opioid release over 24 hours in the event ofcorrect administration is impaired by the nature of the formulation andthe polymer (C) is included in the formulation and formulation iscarried out in accordance with the above-stated processes.

In a preferred embodiment of the dosage form according to the invention,subunits (X) and (Y) are present in multiparticulate form, whereinmicrotablets, microcapsules, micropellets, granules, spheroids, beads orpellets are preferred and the same form, i.e. shape, is selected forboth subunit (X) and subunit (Y), such that it is not possible toseparate subunits (X) from (Y) by mechanical selection. Themultiparticulate forms are preferably of a size in the range from 0.1 to3 mm, preferably of 0.5 to 2 mm.

The subunits (X) and (Y) in multiparticulate form may also preferably bepackaged in a capsule or be press-moulded into a tablet, wherein thefinal formulation in each case proceeds in such a manner that thesubunits (X) and (Y) are also retained in the resultant dosage form.

The multiparticulate subunits (X) and (Y) of identical shape should alsonot be visually distinguishable from one another so that the abusercannot separate them from one another by simple sorting. This may, forexample, be achieved by the application of identical coatings which,apart from this disguising function, may also incorporate furtherfunctions, such as, for example, controlled release of one or moreopioid(s) or provision of a finish resistant to gastric juices on theparticular subunits.

In a further preferred embodiment of the present invention, subunits (X)and (Y) are in each case arranged in layers relative to one another.

The layered subunits (X) and (Y) are preferably arranged for thispurpose vertically or horizontally relative to one another in the dosageform according to the invention, wherein in each case one or morelayered subunits (X) and one or more layered subunits (Y) may be presentin the dosage form, such that, apart from the preferred layer sequences(X)-(Y) or (X)-(Y)-(X), any desired other layer sequences may beconsidered, optionally in combination with layers containing components(a) and/or (b).

Another preferred dosage form according to the invention is one in whichsubunit (Y) forms a core which is completely enclosed by thedelayed-release subunit (X), wherein a separation layer (Z) may bepresent between said layers. Such a structure is preferably alsosuitable for the above-stated multiparticulate forms, wherein bothsubunits (X) and (Y) and an optionally present separation layer (Z),which must satisfy the hardness requirement according to the invention,are formulated in one and the same multiparticulate form.

In a further preferred embodiment of the dosage form according to theinvention, the subunit (X) forms a core, which is enclosed by subunit(Y), wherein the latter comprises at least one channel which leads fromthe core to the surface of the dosage form.

The dosage form according to the invention may comprise, between onelayer of the subunit (X) and one layer of the subunit (Y), in each caseone or more, preferably one, optionally swellable separation layer (Z)which serves to separate subunit (X) spatially from (Y).

If the dosage form according to the invention comprises the layeredsubunits (X) and (Y) and an optionally present separation layer (Z) inan at least partially vertical or horizontal arrangement, the dosageform preferably takes the form of a tablet, a coextrudate or a laminate.

In one particularly preferred embodiment, the entirety of the freesurface of subunit (Y) and optionally at least part of the free surfaceof subunit(s) (X) and optionally at least part of the free surface ofthe optionally present separation layer(s) (Z) may be coated with atleast one barrier layer (Z′) which prevents release of component (c)and/or (e) and/or (d) and/or (f). The barrier layer (Z′) must alsofulfil the hardness conditions according to the invention.

Another particularly preferred embodiment of the dosage form accordingto the invention comprises a vertical or horizontal arrangement of thelayers of subunits (X) and (Y) and at least one push layer (p) arrangedtherebetween, and optionally a separation layer (Z), in which dosageform the entirety of the free surface of the layer structure consistingof subunits (X) and (Y), the push layer and the optionally presentseparation layer (Z) is provided with a semipermeable coating (E), whichis permeable to a release medium, i.e. conventionally a physiologicalliquid, but substantially impermeable to the opioid(s) and to component(c) and/or (d) and/or (f), and wherein this coating (E) comprises atleast one opening for release of the opioid(s) in the area of subunit(X).

A corresponding dosage form is known to the person skilled in the art,for example under the name oral osmotic therapeutic system (OROS), asare suitable materials and methods for the production thereof, interalia from U.S. Pat. No. 4,612,008, U.S. Pat. No. 4,765,989 and U.S. Pat.No. 4,783,337. The corresponding descriptions are hereby introduced as areference and are deemed to be part of the disclosure.

An osmotic dosage form containing an analgesic opioid and a dye as anaversive agent is likewise known to the person skilled in the art fromthe prior art (WO 03/015531). The tablet core preferably consists of twolayers, an opioid-containing layer and a push layer, wherein the pushlayer contains the dye as the aversive agent. The correspondingdescription is hereby introduced as a reference and is deemed to be partof the disclosure.

In a further preferred embodiment of the claimed invention, the subunit(X) of the dosage form according to the invention is in the form of atablet, the edge face and optionally one of the two main faces of whichis covered with a barrier layer (Z′) containing component (c) and/or (d)and/or (f).

The person skilled in the art will understand that the auxiliarysubstances of the subunit(s) (X) or (Y) and of the optionally presentseparation layer(s) (Z) and/or of the barrier layer(s) (Z′) used informulating the dosage form according to the invention will vary as afunction of the arrangement thereof in the dosage form according to theinvention, the mode of administration and as a function of theparticular opioid, of the optionally present components (a) and/or (b)and/or (e) and of component (c) and/or (d) and/or (f), while maintainingrelease of the active ingredient over 24 hours. The materials which havethe requisite properties are in each case known per se to the personskilled in the art.

If release of component (c) and/or (d) and/or (f) from subunit (Y) ofthe dosage form according to the invention is prevented with theassistance of a cover, preferably a barrier layer, the subunit mayconsist of conventional materials known to the person skilled in theart, providing that it contains at least one polymer (C) to fulfil thehardness condition of the dosage form according to the invention.

If a corresponding barrier layer (Z′) is not provided to prevent releaseof component (c) and/or (d) and/or (f), the materials of the subunitsshould be selected such that release of the particular component (c)and/or (d) from subunit (Y) is virtually ruled out.

The materials which are stated below to be suitable for production ofthe barrier layer may preferably be used for this purpose. Preferredmaterials are those which are selected from the group comprisingalkylcelluloses, hydroxyalkylcelluloses, glucans, scleroglucans,mannans, xanthans, copolymers ofpoly[bis(p-carboxyphenoxy)propane:sebacic acid], preferably in a molarratio of 20:80 (marketed under the name Polifeprosan 20®),carboxymethylcelluloses, cellulose ethers, cellulose esters,nitrocelluloses, polymers based on (meth)acrylic acid and the estersthereof, polyamides, polycarbonates, polyalkylenes, polyalkyleneglycols, polyalkylene oxides, polyalkylene terephthalates, polyvinylalcohols, polyvinyl ethers, polyvinyl esters, halogenated polyvinyls,polyglycolides, polysiloxanes and polyurethanes and the copolymersthereof.

Particularly suitable materials may be selected from the groupcomprising methylcellulose, ethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, celluloseacetate, cellulose propionate (of low, medium or high molecular weight),cellulose acetate propionate, cellulose acetate butyrate, celluloseacetate phthalate, carboxymethylcellulose, cellulose triacetate, sodiumcellulose sulfate, polymethyl methacrylate, polyethyl methacrylate,polybutyl methacrylate, polyisobutyl methacrylate, polyhexylmethacrylate, polyisodecyl methacrylate, polylauryl methacrylate,polyphenyl methacrylate, polymethyl acrylate, polyisopropyl acrylate,polyisobutyl acrylate, polyoctatdecyl acrylate, polyethylene, lowdensity polyethylene, high density polyethylene, polypropylene,polyethylene glycol, polyethylene oxide, polyethylene terephthalate,polyvinyl alcohol, polyvinyl isobutyl ether, polyvinyl acetate andpolyvinyl chloride.

Particularly suitable copolymers may be selected from the groupcomprising copolymers of butyl methacrylate and isobutyl methacrylate,copolymers of methyl vinyl ether and maleic acid of high molecularweight, copolymers of methyl vinyl ether and maleic acid monoethylester, copolymers of methyl vinyl ether and maleic anhydride andcopolymers of vinyl alcohol and vinyl acetate.

Further materials which are suitable for formulating the barrier layerare starch-filled polycaprolactone (WO98/20073), aliphaticpolyesteramides (DE 19 753 534 A1, DE 19 800 698 A1, EP 0 820 698 A1),aliphatic and aromatic polyester urethanes (DE 19822979),polyhydroxyalkanoates, in particular polyhydroxybutyrates,polyhydroxyvalerates, casein (DE 4 309 528), polylactides andcopolylactides (EP 0 980 894 A1). The corresponding descriptions arehereby introduced as a reference and are deemed to be part of thedisclosure.

The above-stated materials may optionally be blended with furtherconventional auxiliary substances known to the person skilled in theart, preferably selected from the group consisting of glycerylmonostearate, semi-synthetic triglyceride derivatives, semi-syntheticglycerides, hydrogenated castor oil, glyceryl palmitostearate, glycerylbehenate, polyvinylpyrrolidone, gelatine, magnesium stearate, stearicacid, sodium stearate, talcum, sodium benzoate, boric acid and colloidalsilica, fatty acids, substituted triglycerides, glycerides,polyoxyalkylene glycols and the derivatives thereof.

If the dosage form according to the invention comprises a separationlayer (Z′), said layer, like the uncovered subunit (Y), may preferablyconsist of the above-stated materials described for the barrier layer.The person skilled in the art will understand that release of theopioid(s) and/or opiate(s) or of component (c) and/or (d) from theparticular subunit may be controlled by the thickness of the separationlayer.

Method for Determining Breaking Strength

In order to verify whether a polymer or a wax may be used as component(C) or (D) respectively, the polymer or wax is press-moulded to form atablet with a diameter of 10 mm and a height of 5 mm using a force of150 N at a temperature which at least corresponds to the softening pointof the polymer or wax and is determined with the assistance of a DSCdiagram of the polymer or wax. Using tablets produced in this manner,breaking strength is determined with the apparatus described below inaccordance with the method for determining the breaking strength oftablets published in the European Pharmacopoeia 1997, page 143, 144,method no. 2.9.8. The apparatus used for the measurement is a “Zwick Z2.5” materials tester, Fmax=2.5 kN, draw max. 1150 mm with the setupcomprising a column and a spindle, clearance behind of 100 mm, a testspeed of 0.1800 mm/min and testControl software. Measurement wasperformed using a pressure piston with screw-in inserts and a cylinder(diam. 10 mm), a force transducer, (Fmax. 1 kN, diameter=8 mm, class 0.5from 10 N, class 1 from 2 N to ISO 7500-1, with manufacturer's testcertificate M to DIN 55350-18, Zwick gross force Fmax=1.45 kN) (allapparatus from Zwick GmbH & Co. KG, Ulm, Germany).

The tablets deemed to be resistant to breaking under a specific loadinclude not only those which have not broken but also those which mayhave suffered plastic deformation under the action of the force.

The breaking strength of the dosage forms according to the invention isdetermined using the same measurement method.

The invention is explained below with reference to Examples. Theseexplanations are given merely by way of example and do not restrict thegeneral concept of the invention.

EXAMPLE 1 a) Production of an Abuse-Proofed Tablet Containing Oxycodone

The quantities of oxycodone hydrochloride, polyethylene oxide powder andhydroxypropylmethylcellulose (Metholose 90 SH 100 000) as thedelayed-release matrix material listed in Table 1 were mixed in afree-fall mixer. The tabletting tool, which consists of die, top punchand bottom punch with a diameter of 10 mm, was heated to 90° C. in aheating cabinet. 600 mg portions of the powder mixture werepress-moulded by means of the heated tool, the pressure being maintainedfor at least 15 seconds.

TABLE 1 Complete Components Per tablet batch Oxycodone HCl  80.0 mg 40.0 g Polyethylene oxide, NF, MW 7 000 000 470.0 mg 235.0 g (PolyoxWSR 303, Dow Chemicals) Hydroxypropylmethylcellulose 100 000 mPas  50.0mg  25.0 g (Metholose 90 SH 100 000) Total weight 600.0 mg 300.0 g

The breaking strength of the tablets is determined using theabove-described method. No breakage occurred when a force of 500 N wasapplied. The tablets could not be comminuted using a hammer, nor withthe assistance of a pestle and mortar.

In vitro Release from the Tablets Produced According to a)

In vitro release of oxycodone hydrochloride from the tablets producedaccording to a) was determined in a paddle stirrer apparatus with sinkeraccording to the method described in the European Pharmacopoeia. Thetemperature of the release medium was 37° C. and the rotational speed ofthe stirrer 75 min⁻¹. The release medium used was intestinal juice, pH6.8. The quantity of oxycodone hydrochloride released in each case intothe dissolution medium at any one time was determined byspectrophotometry. The percentage released quantity, relative to thetotal quantity of oxycodone hydrochloride, at each point in time isshown in Table 2.

TABLE 2 Time, minutes Released quantity, wt. % 30 11 240 40 480 61 72076 1080 92 1440 97

1. An abuse-proofed oral dosage form with controlled opioid release foronce daily administration, comprising at least one opioid with potentialfor abuse (A) and/or one of the physiologically acceptable compoundsthereof, polyethylene oxide having a molecular weight of 0.5 million to15 million (C), optionally delayed release auxiliary substances,optionally physiologically acceptable auxiliary substances (B),optionally a wax (D) and optionally at least one delayed-releasecoating, said abuse-proofed oral dosage form exhibiting a breakingstrength of at least 500 N.
 2. A dosage form according to claim 1,wherein the opioid is at least one opioid selected from the groupconsisting of oxycodone, hydromorphone, morphine, tramadol, thestereoisomers thereof, the enantiomers thereof, the diastereomersthereof in any desired mixtures and the physiologically acceptablecompounds thereof.
 3. The dosage form of claim 2, wherein saidphysiologically acceptable compounds thereof are salts, solvates, estersor ethers.
 4. A dosage form according to claim 1, wherein said at leastone opioid is selected from the group consisting of(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol,(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,(1RS,2RS)-3-(2-dimethylaminomenthyl-cyclohexyl)phenol, physiologicallyacceptable salts thereof, physiologically acceptable enantiomersthereof, stereoisomers thereof, diastereoisomers thereof, and racematesthereof and ethers, esters or amides thereof.
 5. A dosage form accordingto claim 1, wherein said at least one opioid is selected from the groupconsisting of hydrocodone, the stereoisomers thereof, the enantiomersthereof, the diastereomers thereof in any desired mixtures and thephysiologically acceptable compounds thereof.
 6. The dosage form ofclaim 5, wherein said physiologically acceptable compounds thereof aresalts, solvates, esters or ethers.
 7. A dosage form according to claim1, in the form of a tablet.
 8. A dosage form according to claim 1,wherein said wax (D) is present and is at least one natural,semi-synthetic or synthetic wax with a softening point of at least 60°C.
 9. A dosage form according to claim 8, wherein said wax (D) iscarnauba wax or beeswax.
 10. A dosage form according to claim 1, whereinsaid active ingredient is present in a delayed-release matrix.
 11. Adosage form according to claim 1, wherein component (C) and/or component(D) also serves as an additional delayed-release auxiliary substance.12. A dosage form according to claim 1, comprising said delayed-releasecoating.
 13. A dosage form according to claim 1, comprising at least oneof the following components (a)-(f) as an auxiliary substance (B): (a)at least one substance which irritates the nasal passages and/orpharynx, (b) at least one viscosity-increasing agent, which, with theassistance of a necessary minimum quantity of an aqueous liquid, forms agel which optionally remains visually distinguishable when introducedinto a further quantity of an aqueous liquid, (c) at least oneantagonist for said at least one opioid, (d) at least one emetic, (e) atleast one dye as an aversive agent, (f) at least one bitter substance.14. A dosage form according to claim 13, wherein saidviscosity-increasing agent is present and comprises at least one polymerselected from the group consisting of carboxymethylcellulose sodium,polyacrylic acid, locust bean flour, pectin, waxy maize starch,alginate, guar flour, iota-carrageenan, karaya gum, gellan gum,galactomannan, tara stone flour, propylene glycol alginate, hyaluronate,tragacanth, tara gum, fermented polysaccharide welan gum and xanthan.15. A dosage form according to claim 1, wherein component (C), inaddition to increasing the breaking strength of the dosage form, alsofunctions as a viscosity-increasing agent.
 16. A dosage form accordingto claim 1, wherein component(s) (C) and optionally (D) are present insufficient amounts to produce a dosage form exhibiting a breakingstrength of at least 500 N.
 17. A dosage form according to claim 1,exhibiting a breaking strength of at least 1000N.
 18. A process for theproduction of the dosage form of claim 1, which comprises (1) mixingcomponents (A), (C), optionally an auxiliary substance (B) selected fromthe group consisting of (a) at least one substance which irritates thenasal passages and/or pharynx, (b) at least one viscosity-increasingagent, which, with the assistance of a necessary minimum quantity of anaqueous liquid, forms a gel which optionally remains visuallydistinguishable when introduced into a further quantity of an aqueousliquid, (c) at least one antagonist for said at least one opioid, (d) atleast one emetic, (e) at least one dye as an aversive agent, (f) atleast one bitter substance, optionally (D) and optionallydelayed-release matrix compounds to form a mixture and (2) forming theresultant mixture, optionally after pelletisation, into the dosage formby application of force, with preceding or simultaneous heating to atleast the softening point of component (C), of sufficient magnitude andfor a sufficient time until the dosage form exhibits a breaking strengthof at least 500N, and optionally applying a delayed-release coating. 19.The process of claim 18, wherein said pelletisation is performed and isperformed by a melt method.
 20. The process of claim 18, where saidpelletisation is performed and is performed by wet method.
 21. Theprocess of claim 18, wherein (1) a mixture containing components (A),(C), optionally (B) and optionally (D) and optionally delayed-releasematrix compounds is formed into formed articles by application of force,(2) the formed articles obtained are optionally singulated andoptionally in each case graded by size and (3) after or during heatingto at least the softening point of component (C), the formed articlesare exposed to a force of sufficient magnitude and for a sufficient timeuntil the formed articles exhibit a breaking strength of at least 500 N,(4) the formed articles are optionally provided with an optionallydelayed-release coating and the formed articles are optionally all mixedtogether again.
 22. The process of claim 21, wherein said breakingstrength is at least 1000N.
 23. A dosage form obtained by the process ofclaim
 18. 24. A method of treating pain in a patient in need of suchtreating, said method comprising administering to said patient a dosageform according to claim
 1. 25. A method of treating pain in a patient inneed of such treating, said method comprising administering to saidpatient a dosage form according to claim 23.